Question: 

The analgetic effect of acetylsalicylic acid (ASA) has long been contributed to the irreversible inhibition of cyclooxygenase (COX), exclusively. We have previously shown that ASA also directly inhibits the capsaicin receptor TRPV1 in native DRG neurons [1] as well as in a heterologous expression system [2]. We now investigated the pharmacology of ASA and other salicylic acid derivatives on inhibition of the capsaicin-activated TRPV1.

Methodology: 

HEK293 cells were transiently transfected with a vector containing a GFP-coupled rat TRPV1 insert, loaded with FURA-2-AM and investigated using calcium microfluorimetry. Cells were activated repetitively with capsaicin (300nM for 30s), 30s before and during the second capsaicin stimulus ASA, methyl salicylate (MS), salicylic acid (SAc), the competitive TRPV1 antagonist capsazepine (CPZ), vehicle or combinations of those were applied.

Results: 

ASA up to 100mM alone did not affect intracellular calcium but significantly and dose-dependently reduced capsaicin responses up to a maximal inhibition by about 70% at 0.3mM (p<0.001, unpaired T-Test vs. vehicle). However, further increasing the ASA concentration reduced its antagonistic effect on TRPV1. A similar kinetic with a higher inhibitory capacity at lower concentrations was observed for MS and SAc (p<0.01). Furthermore, co-application of ASA at concentrations above 10mM with the competitive TRPV1 antagonist CPZ and capsaicin reduced the amount of inhibition whereas lower ASA concentrations did not, reminiscent of co-agonistic effect of ASA at TRPV1.

Conclusion: 

These results suggest a new and complex mechanism for the action of ASA-like drugs directly at the nociceptive TRPV1 receptor. We suggest a direct and immediate interaction of those drugs with TRPV1 via mechanisms involving antagonistic at low as well as co-agonistic effects at the capsaicin receptor at higher concentrations that do not dependent on acetylation of COX.

1. Greffrath, W., et al.: Acetylsalicylic acid reduces heat responses in rat nociceptive primary sensory neurons-evidence for a new mechanism of action. Neurosci Lett, 2002.320(1–2): 61–4.

2. Geörg K., et al.: Acetylsalicylic acid is a pharmacological antagonist at the capsaicin-receptor TRPV1 - further evidence for a new mechanism of action of ASA-like drugs? Acta Physiologica, 2011. 201 (Suppl.682)(P 179): p. 261.